Submissions for variant NM_000059.4(BRCA2):c.7471C>T (p.Gln2491Ter)

dbSNP: rs80358971

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113766	SCV000301167	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113766	SCV000327666	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509717	SCV000607780	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	The p.Q2491* pathogenic mutation (also known as c.7471C>T), located in coding exon 14 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7471. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This alteration has been reported in one Czech high-risk breast and/or ovarian cancer family (Machackova E et al. BMC Cancer. 2008 May;8:140). It has also been identified in 1/119 Chinese high-risk breast and/or ovarian cancer patients (Kwong A et al. Breast Cancer Res. Treat. 2009 Oct;117:683-6). Of note, this alteration is also designated as 7699C>T in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000496673	SCV001586229	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 18489799, 22970155, 27157322, 29446198). This variant is also known as 7699C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 52339). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln2491*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product.
MGZ Medical Genetics Center	RCV000113766	SCV002580573	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-12-20	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113766	SCV000147100	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496673	SCV000587894	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357153	SCV001552524	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Gln2491* variant was identified in 2 of 1500 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Kwong 2012, Machackova 2008). The variant was also identified in dbSNP (ID: rs80358971) as "With Pathogenic allele", ClinVar (classified as pathogenic by ENIGMA, Ambry Genetics and three other submitters), COGR, LOVD 3.0 (4x ), UMD-LSDB (1x as causal), BIC Database (2x with clinical importance), ARUP Laboratories (definitely pathogenic), and in Zhejiang University Database. The variant was not identified in Cosmic, or MutDB databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln2491* variant leads to a premature stop codon at position 2491 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in breast or ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.